Hydroxy isocoumarins

Isocoumarin, 3,4-dihydro- — see Isochroman-l-one Isocoumarin, 8-hydroxy-3-methyI-occurrence, 3, 677 Isocoumarin, 8-methoxy-3-methyI-reactions... 

Camponotus rufipes W-HG Trail following 3,4- Dihydro - 8 -hydroxy- 3,7- dim e thyl-isocoumarin 120 [167]... 

Camponotus silvicola W-HG Trail following (3R)-(-)-3,4-Dihydro-8-hydroxy-3,5,7-trimethyl-isocoumarin 121 [167]... 

Recently, little work has been done with the endophytes of gym-nosperms. The isolation of Chaetomium chiversii from Ephedra fasciculata in the Sonoran desert of southwestern USA, led to two new isocoumarins, chaetochiversins A (64) and B (65) three known isocoumarins eugenetin (66), 6-methoxy-methyleugenin (67), and 6-hydroxy-methyleugenin (68) ... 

Isocoumarins are less numerous than coumarins in nature. The acetylenic isocoumarin capillarin (225) is present in at least two Artemisia species and a fungus, Marasmius ramealis, produces 8-hydroxy-3-methylisocoumarin (226). 

An alternative approach to the synthesis of isocoumarins which probably proceeds through the intermediacy of 2-carboxybenzyl ketones is based on the oxidative cleavage of indan-1-ones (76JCS(P1)1438). Although ozonolysis of the silyl enol ether (505) leads to the 2-hydroxy-2-methylindan-l-one (506), periodate oxidation of which gives the isocoumarin, a more convenient and direct route involves ozonolysis of the enol trifluoroacetate (Scheme 182). This synthesis is especially attractive for the preparation of isotopically labelled isocoumarins, since the precursors of the indanones, arylpropanoic acids or acrylophenones, are readily available bearing labels at specific sites. 

Coumarins and isocoumarins appear to be of varied origins. Simple coumarins, such as umbelliferone, are formed by the shikimic acid pathway in which hydroxylation of p-hydroxycinnamic acid occurs. Other coumarins, for example alternariol (690), are derived from a polyketide unit, as are a number of chromanones, chromones, pyranones and isocoumarins (B-78MI22400). The biosynthesis of 5-hydroxy-2-methylchromone has been shown to involve the chromanone (60JCS654). However, isocoumarins are also derived from the mixed acetate-shikimate route, through initial cyclization of the polyketide and subsequent lactonization. 

Hydroxypyridine (201) itself possesses latent 1,3-dipolar character because of tautomerism involving 1-protiopyridinium 3-oxide (202). Aprotic diazotization of anthranilic acid in the presence of 201 gives two heterocyclic products [196 (20%) and 203 (23%)] which were isolated in separate experiments run under almost identical conditions.103,105 Formation of the bis-adduct 196 must involve cycloaddition of benzyne to 202 and N-phenylation and there is some evidence from related additions to 2//-phthalazin-1 -one (208) that the steps occur in this order.3 7b Formation of the isocoumarin structure 203 apparently involves electrophilic substitution of 201 by the benzyne precursor 5, followed by lactonization. From 3-hydroxy-6-methylpyridine compounds analogous to 196 and 203 were also obtained (10 and 29%, respectively). 3-Hydroxyquinoline afforded only the corresponding isocoumarin 204 (20%) whereas 4-hydroxyisoquinoline gave 4-phenoxyisoquinoline (12%) and the bis-adduct 205 (12%) with benzyne.103,105... 

Isocoumarin may be synth zed in high yield by heating an o-ethoxyvinyl-benzoate ester with mineral add. An o-hydroxy (or ethoxy)malonyIidene mono-nitrile gives a high yield of a fused pyran-2-one by heating with hydrochloric acid. 

Dihydro-SH-2,3-beiizodiazepiii-l-ones. A soln. of the startg. isocoumarin and 2 moles 95%-hydrazine hydrate in ethanol refluxed 3-4 hrs. with occasional addition of extra hydrazine hydrate -> l,2-dihydro-4-(4-hydroxy-2-methylphenyl)-5H-... 

Dihydro-6-hydroxy-3-methyl isocoumarin-7.8-dicarboxylic acid... 

Obtained by decarboxylation of 6,8-dihy-droxy-3-(2-hydroxy-4-methylphenyl) OH isocoumarin(m.p. 201-202°) withreflux-ing 10% aqueous potassium hydroxide solution for 6 h (90%) [5482],... 

Mellein (19) has been taken as the parent compound for simple isocoumarins. Thus the commonly occurring 3,4-dihydro-8-hydroxy-6-methoxy-3-methylisocoumarin (53) is known as 6-methoxymellein. This greatly aids discussion of these compounds. 

Nozawa, K., S. Nakajima, M. Yamada, and K.-I. Kawai. Synthesis of Two Microbial Metabolites, 5-Chloro-3,4-dihydro-8-hydroxy-6-methoxy-3-methyl-isocoumarin and 8-Hydroxy-6-methoxy-3-methylisocoumarin. Chem. Pharm. Bull. (Japan) 28, 1622 (1980). 

ScHMALLE, H.W., O.H. Jarchaw, B.M. Hausen, and K.H. Schulz 3,4-Dihydro-8-hydroxy-3-(4-Hydroxyphenyl)isocoumarin, Hydrangenol. Acta Crystallogr. 38B, 2938 (1982). 

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